Insect maturation inhibitors

ABSTRACT

Certain arylterpenoid compounds having excellent potential as insect control agents. The compounds are highly active as eclosion inhibiting agents against four species of flies and three species of mosquito.

This application is a continuation-in-part of application Ser. No. 498,165, filed Aug. 16, 1974, now abandoned..].

.Iadd.This is a continuation, of application Ser. No. 141,620, filed Apr. 18, 1980 now abandoned which is a continuation of application Ser. No. 002,083 filed Jan. 9, 1979 now abandoned, which in turn is a reissue application of U.S. Pat. No. 4,002,769, which is a continuation-in-part of abandoned application Ser. No. 498,165, filed Aug. 16, 1974.

.[.This application is a continuation-in-part of application Ser. No. 498,165, filed Aug. 16, 1974, now abandoned..].

This invention relates to certain arylterpenoid compounds useful in the control of insects and, more particularly, in the control of flies and mosquitoes.

A number of arylterpenoid compounds have exhibited juvenile hormone activity against several insect species as previously described by Schwarz et al. (Life Sci. 10, Part II, Biochem. Gen. Mol. Biol., 1125-1132, 1971 and J. Econ. Entomol., 67, 177-180, 1974). However, as the results described in the above two publications adequately demonstrate, one cannot use structural relationships to predict activity with even a modicum of reliability. For example, no correlation in activity was found between geometric isomers or between compounds in which the only structural difference was the position of the substituent on the aromatic portion of the molecule.

Consequently, it was unexpected and quite surprising when found that the arylterpenoid compounds of this invention having closely related structures display extremely high activity against several species of Diptera.

It is an object of this invention to provide compounds that inhibit the eclosion of adult flies and mosquitoes from pupae and interfere with insect development when applied directly to the insect larvae or pupae.

It is a further object of this invention to provide compounds that prevent emergence of insects from the larvae or pupae when they are applied to the natural growth media of the insects.

A further object of this invention is to provide compounds that inhibit the eclosion of flies and mosquitoes when they are incorporated in animal feces by feeding the compounds to cattle and other animals.

A still further object of this invention is to provide compounds that inhibit the eclosion of flies and mosquitoes when sprayed in appropriate animal housing areas.

The compounds of this invention have the following structural formula: ##STR1## in which A is alkyl having 1 to 5 carbon atoms, preferably ethyl isopropyl or sec.-butyl; alkoxy having 1 to 4 carbon atoms; alkylthio having 1 to 4 carbon atoms; nitro or 3,4-methylene dioxy; more preferably A is in the para position and most preferably A is in the para position and is alkyl having 1 to 5 carbon atoms; R and R¹ are independently methyl or ethyl, preferably methyl; and R² is alkyl having 1 to 4 carbon atoms, preferably methyl or ethyl, more preferably methyl. The compounds will inhibit eclosion of flies and mosquitoes when applied in a variety of ways including application directly to the insect larvae or pupae, application to the natural growth media such as animal feces, incorporation of the compounds in the diets of livestock and poultry and by spray application in appropriate animal housing areas.

This invention is particularly concerned with the preparation and activity of the arylterpenoid compounds against the house fly, Musca domestica (L).; the face fly, Musca autumnalis DeGeer, the stable fly, Stomoxys calcitrans (L.); the horn fly, Haematobia irritans (L.); and the mosquito, Anopheles quadrimaculatus. The structure and names of several compounds are listed in Table 1. All of these compounds were tested by applying them directly to the insect pupae while some of them were tested by feeding to cattle and by spraying the compounds on rearing pans containing artificial insect growth media. In general, the compounds of this invention can be prepared according to the following outline. ##STR2## wherein A, R, R¹ and R² are as defined.

The benzyl alcohols used as starting materials are freed of contaminating ortho isomers by spinning band distillation. The chlorides and triphenylphosphonium salts are prepared in the usual manner and are obtained in nearly quantitative yields. The Wittig reactions (Organic Reactions, Vol. 14, pages 270-490, John Wiley and Sons, Inc., New York, 1965) are carried out in absolute ethanol with sodium ethoxide as the base and yield 80% of a 60:40 mixture of Z and E isomers. The alkoxymercuration-demercuration reaction is carried out in 80-90% yields by using the appropriate alcohol (R² OH) as the solvent (J. Med. Chem. 12, 191-192, 1969). The remaining double bond was hydrogenated at atmospheric pressure with PtO₂ as the catalyst.

In order to illustrate a typical preparation, the following is a detailed example of the preparation of compound 4 in Table 1.

PREPARATION OF COMPOUND 4 p-Isopropylbenzylchloride

p-Isopropylbenzyl alcohol (128 g., 0.85 mol.) was added dropwise with stirring to 400 ml of concentration HCl, while the temperature was kept between 25° and 30° C. The reaction mixture was stirred for 4 hours and worked up by pouring into 500 ml of ice water and extracting with hexane. The hexane extracts were washed to neutrality yielding 135 g. (93%) of p-Isopropylbenzylchloride, bp 108° C/18 mm. n_(D) ²⁵ =1.5212

p-Isopropylbenzyltriphenylphosphonium chloride

p-Isopropylbenzylchoride (168.5 g, 1 mol.) and triphenylphosphine (275 g, 1.05 mol.) were refluxed overnight in acetonitrile (600 ml). Approximately 300 ml of acetonitrile were removed in vacuo and 500 ml ether was added. The salt was allowed to crystallize and the salt was filtered off and washed with ether. Yield of the first crop of crystals was 388 g (90%) of desired salt. Some additional salt could be recovered from the mother liquors.

4,8-Dimethyl-1-(p-isopropylphenyl)-nona-1,7-diene

To a stirred solution of sodium (21 g, 0.9 at) in 1500 ml of absolute ethanol was added 388 g of p-isopropylbenzyltriphenylphosphonium chloride. The resulting phosphorane solution was cooled to 15°-20° C. (The light orange color fades when the temperature is lowered!) Freshly vacuum distilled citronellal (150 g, 1 mol.) was added dropwise while keeping the reaction mixture at reflux for 4 hours. The cooled reaction mixture was filtered to remove sodium chloride, most of the alcohol was distilled off in vacuo and 500 ml of hexane was added. The triphenylphosphineoxide was allowed to crystallize and filtered off. The solvents were removed from the mother liquors under vacuum and another 500 ml of hexane added. Cooling afforded another crop of triphenylphosphineoxide. The hexane was again evaporated and the residue distilled yielding, after a small forerun of isopulegol (a contaminant of citronellal), 200 g (82%) of the desired product. bp. 150°-145° C/0.1 mm. Ratio of E to Z is app. 40:60. n_(D) ²⁵ =1.5172.

4,8-Dimethyl-1-(p-Isopropylphenyl)-non-1-ene

To a stirred solution of 16 g (0.7 g at) of sodium in 600 ml of liquid ammonia was added dropwise a solution of 93 g (0.34 mol.) of 4,8-dimethyl-1-(p-isopropylphenyl)nona-1,7-diene in 125 ml of anhydrous tetrahydrofuran. Total addition time was one hour. The excess sodium was destroyed by the cautious addition of methanol. Then 200 ml of hexane were added and the ammonia was allowed to evaporate. To the residue a saturated solution of NH₄ Cl was added cautiously. The organic layer was separated, and the aqueous layer was diluted with water and extracted twice with hexane. The combined hexane layers were washed with water, dilute HCl, brine and then dried. Evaporation of the hexane and distillation of the residue yielded the title product. Yield was 88 g (94%), bp 130°-135° C/0.1 mm. n_(D) ²⁵ =1.4938.

2-Ethoxy-9-(p-Isopropylphenyl)1-2,6Dimethylnonane

To a stirred solution of 27 g (0.1 mole) of 4,8-dimethyl-1-(p-isopropylphenyl)-non-1-ene in 125 ml absolute ethanol was added portionwise at room temperature 34 g (0.11 mole) of mercuric acetate. The mixture was stirred for 1 hour, at which time all mercuric acetate had dissolved. Then the reaction mixture was cooled to 5° and 15 g of NaOH in 100 ml 80% ethanol was added dropwise, keeping the reaction mixture below 25° C. Then 3.5 g of NaBH₃ was added portionwise, again keeping the mixture below 25° C. Hexane (200 ml) and 200 ml water were then added, and mixture stirred until the mercury had coagulated. The organic layer separated and the aqueous layer extracted with two 100 ml portions of hexane. The combined hexane layers were extracted with water, dilute HCl, water and brine. The organic layer was then dried and the hexane removed in vacuo. The residue was distilled at 145° C/ 01 mm to yield 28.5 g (90%) of title compound. n_(D) ²⁵ =1.4806.

Activity of the compounds against face and house flies was determined by the procedure of Miller et al (J. Econ. Entomol. 63, 853-855, 1970) and activity against horn flies was determined by the procedure of Harris et al (J. Econ. Entomol. 66, 1099-1102, 1973). Essentially, these procedures involve seeding day old larvae or eggs in either fresh cattle feces or in an artificial medium that contained the compound being tested. The results are shown in Table 2. Activity of the compounds against stable and house flies was also determined by topical application of an acetone solution of the compound being tested to newly ecdysed pupae as described in J. Econ. Entomol., 65, 1361-1364, 1972.

Compounds 2 and 4 in Table 1 were further tested by feeding them to cattle and seeding fly larvae or eggs in the feces of the thus treated cattle. Face and house fly larvae were seeded in the feces of the treated cattle and tested according to the procedures of Miller and Uebel (J. Econ. Entomol., 67, 69-70, 1974), while stable and horn fly eggs were seeded in the feces of the treated cattle and tested according to the procedures of Harris et al (J. Econ. Entomol., 66, 1099-1102, 1973). The results of these feeding tests are shown in Table 3.

Spray tests were also conducted according to the procedure described by Wright (J. Econ. Entomol., 65, 1361-1364, 1972). An appropriate quantity of an emulsifiable concentrate containing 25 parts of the candidate compound, 65 parts of xylene, and 10 parts of a nonionic surfactant, octyl phenoxy polyethoxy ethanol (Triton X-100) in 100 ml of water was sprayed on rearing pans containing artificial media and four-day old house fly larvae or six-day old stable fly larvae. The rearing pans were then placed in screened cages for adult eclosion. The eclosed adults were counted 14 days after the treatment and percentage inhibition of eclosion determined.

As shown in Table 2, the tested compounds of this invention had very high activity against the face fly when tested by seeding larvae or eggs in the natural growth media of the flies by the method set forth above. Compounds 1 and 2 exhibited high activity against the horn fly. Since the face fly is generally more resistant than the horn fly to the activity of maturation inhibiting compounds and since compounds 3 and 4 had shown high activity against the face fly, they were not tested against the horn fly.

Among the four species of flies used for the purpose of this invention, the generally established order of susceptability to the action of maturation inhibiting compounds is, from most resistant to least resistant, house fly, face fly, stable fly, and horn fly. Of course, exceptions to this general order occasionally occur.

Topical application in acetone solution of from 0.1 to 0.01 μg of each of the six compounds to stable and house fly pupae sufficed to prevent eclosion.

The results of the feeding tests with compounds 2 and 4 are shown in Table 3. In these tests, cattle were fed for a week, but the manure for test purposes was collected only on the last 5 days of the feeding week. Compound 4 exhibited the most activity against all four fly species.

Both compounds 2 and 4 exhibited excellent activity in the spray tests, especially at application rates of 10 mg/sq ft and higher. The results are shown in Table 4.

In addition to activity against the four species of flies, the recited compounds of this invention were tested and exhibited remarkable activity against the mosquito, Anopheles quadrimaculatus and other two species indicated. The very low LC-50, that is, the concentration (lethal concentration) in water that inhibits eclosion of 50% of the mosquito pupae, of compounds 3 and 4 is considered especially remarkable by skilled workers in the field of insects affecting man. The results are shown in Tables 5 and 6. The testing procedure used is a routine method and is generally described in Mosquito News 31, 540-543, 1971.

The activity of the compounds of this invention against flies and mosquitoes was very surprising because when they were tested against conventional screening insects, T. molitor and O. fasciatus, they exhibited extremely low activity. In fact, compound 4 showed no activity whatsoever, and the other compounds showed, at best, only moderate activity. This is important to note because usually when compounds or other materials are screened against T. molitor and O. fasciatus and found not active or only slightly active, they are not considered worth testing against other insects because these two screening insect species are more susceptible to juvenile hormone type materials than most other insects. Consequently, the remarkably high activity of the compounds of this invention against the four species of flies and against the three species of mosquito was completely unpredicted and unexpected.

                                      TABLE 1                                      __________________________________________________________________________     Compound number                                                                          Structures and names of arylterpenoid compounds                      __________________________________________________________________________                ##STR3##                            2-methoxy-9-(p-ethylphenyl)                                                    - 2,6-dimethylnonane            2                                                                                         ##STR4##                            2-ethoxy-9-(p-ethylphenyl)-                                                     2,6-dimethylnonane             3                                                                                         ##STR5##                            2-methoxy-9-(p-isopropylphe                                                    nyl)- 2,6-dimethylnonane        4                                                                                         ##STR6##                            2-ethoxy-9-(p-isopropylphen                                                    yl)- 2,6-dimethylnonane         5                                                                                         ##STR7##                            2-methoxy-9-(p-methylphenyl                                                    )- 2,6-dimethylnonane           6                                                                                         ##STR8##                            2-ethoxy-9-(p-methylphenyl)                                                    - 2,6-dimethylnonane            7                                                                                         ##STR9##                            2-methoxy-9-(p-n-propylphen                                                    yl)- 2,6-dimethylnonane         8                                                                                         ##STR10##                           2-ethoxy-9-(p-n-propylpheny                                                    l)- 2,6-dimethylnonane          9                                                                                         ##STR11##                           2-methoxy-9-(p-sec.                                                            butylphenyl)- 2,6-dimethyln                                                    onane                           10                                                                                        ##STR12##                           2-ethoxy-9-(p-t-sec.                                                           butylphenyl)- 2,6-dimethyln                                                    onane                           11                                                                                        ##STR13##                           2-methyl-9-(p-t-butylphenyl                                                    )- 2,6-dimethylnonane           12                                                                                        ##STR14##                           2-ethoxy-9-(p-t-butylphenyl                                                    )- 2,6-dimethylnonane           __________________________________________________________________________

                  TABLE 2                                                          ______________________________________                                         Juvenile hormone activity of arylterpenoid compounds                           incorporated in the natural growth media of flies                                              % inhibition of eclosion of adults.sup.a                       Com-    Dosage  from pupae                                                     pound   (ppm)   Face fly    House fly                                                                             Horn fly                                    ______________________________________                                         1       0.1                         93                                                 1.0      94         37     100                                                 5.0     100         73                                                         10.0    100         89     100                                         2       0.1                         55                                                 1.0      95         61      95                                                 5.0      98         77                                                         10.0    100         88     100                                         3       0.1     100         12                                                         1.0     100         87                                                         5.0     100         100                                                        10.0    100         97                                                 4       0.1      84          8                                                         1.0     100         72                                                         5.0      98         100                                                        10.0    100         100                                                5       0.1                                                                            1.0      39         12                                                         5.0                                                                            10.0     40          0                                                 6       0.1                                                                            1.0      44         14                                                         5.0                                                                            10.0    100         88                                                 7       0.1                                                                            1.0                                                                            5.0                                                                            10.0     90         79                                                 8       0.1                                                                            1.0                                                                            5.0                                                                            10.0     88         63                                                 9       0.1                                                                            1.0     100         54                                                         5.0                                                                            10.0    100         95                                                 10      0.1                                                                            1.0     100         26                                                         5.0                                                                            10.0    100         99                                                 11      0.1                                                                            1.0                                                                            5.0                                                                            10.0     4           1                                                 12      0.1                                                                            1.0                                                                            5.0                                                                            10.0     28         10                                                 ______________________________________                                          .sup.a Adjusted for control inhibition by Abbott's formula, J. Econ.           Entomol., 18, 265-7, 1925.                                               

                  TABLE 3                                                          ______________________________________                                         Development of face flies, house flies, stable flies,                          and horn flies in feces from cattle fed 3 arylter-                             penoid compounds.                                                              Dosage         % Inhibition of adult eclosion                                  (mg/kg)        from pupae.sup.a                                                Com-    body       Face    House   Stable Horn                                 pound   wt/day)    fly     fly     fly    fly                                  ______________________________________                                         2       2.5        100     80                                                          1.25                       100    100                                          1.0        100     65                                                          0.5         88     38      100     79                                          0.25        59     19              82.sup.b                                    0.125       0       1                                                  3       0.5        100     68                                                          0.25       100     61                                                          0.125       99     42                                                  4       2.5        100     95                                                          1.25                                                                           1.0        100     95                                                          0.5        100     64      100    100                                          0.25       100     54      100.sup.b                                                                             100.sup.b                                    0.125       97     20       50.sup.c                                                                              95.sup.c                            ______________________________________                                          .sup.a Adjusted for control inhibition by Abbott's formula, J. Econ.           Entomol., 18, 265-267, 1925.                                                   .sup.b Concentrations obtained by diluting 1 pt feces from cattle fed at       rate of 0.5 mg with 1 pt of control feces.                                     .sup.c Concentrations obtained by diluting 1 pt feces from cattle fed at       rate of 0.5 mg with 3 pt of control feces.                               

                  TABLE 4                                                          ______________________________________                                         Development of stable fly and house fly from medium                            treated by surface sprays of 3 arylterpenoid                                   compounds.                                                                            % inhibition of stable fly and house fly eclosion                              due to treatment with indicated compound                                Rate of  1           3           6                                             application                                                                             Stable  House   Stable                                                                               House Stable                                                                               House                               (mg/ft.sup.2)                                                                           fly     fly     fly   fly   fly   fly                                 ______________________________________                                         500      100     100     100   99    100   100                                 250      100     100     100   99    100   100                                 100      100      99     100   99    100   100                                 40       100     100     100   97    100   100                                 20       100     100     100   77    99    100                                 10       100     100     100   72    99     97                                 5         90      87      90   43    81     43                                 1         58      54      3    38    71                                        0.5       8       11                 65                                        0.1                                  20                                        ______________________________________                                    

                  TABLE 5                                                          ______________________________________                                         Development inhibiting activity of arylterpenoid                               compound against Anopheles quadrimaculatus                                                 Amount of compound needed to obtain                                Com-        indicated lethal concentration                                     pound       LC-50 (ppm) LC-90 (ppm)                                            ______________________________________                                         1           0.0014      0.0061                                                 2           0.0035      0.0245                                                 3           0.0004      0.0015                                                 4           0.0004      0.0024                                                 ______________________________________                                    

                  TABLE 6                                                          ______________________________________                                         Developmental inhibiting activity of arylterpenoid                             compound against Anopheles quadrimaculatus,                                    Anopheles albimanus and Aedes taeniorhynchus                                   Amount of compound needed to obtain indicated                                  lethal concentration                                                           LC.sub.90 in p.p.m.                                                            Com-   Anopheles    Anopheles   Aedes                                          pound  quadrimaculatus                                                                             albimanus   taeniorhynchus                                 ______________________________________                                         1      0.0061       0.0140      0.0011                                         2      0.0245       0.0216      0.0014                                         3      0.0019       0.0005      0.0007                                         4      0.0024       0.0005      0.0009                                         ______________________________________                                     

We claim:
 1. A method of inhibiting the eclosion of fly pupae comprising adding to the natural growth media of said pupae from about 0.1 to about 10.0 ppm of a compound of the general formula: ##STR15## in which A is alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, or nitro; R and R¹ are independently methyl or ethyl; and, R² is alkyl having 1 to 4 carbon atoms.
 2. The method of claim 1 in which A is in the para position.
 3. The method of claim 1 in which the pupae is that of flies selected from the species consisting of the face fly, the house fly and the horn fly.
 4. The method of claim 3 in which the compound is selected from the group consisting of 2-methoxy-9-(p-ethylphenyl)-2,6-dimethylnonane; 2-ethoxy-9-(p-ethylphenyl)-2,6-dimethylnonane; 2-methoxy-9-(p-isoprophenyl)-2,6-dimethylnonane; 2-ethoxy-9-(p-isoproplyphenyl)-2,6-dimethylnonane; 2-methoxy-9-(p-sec.-butylphenyl)-2,6-dimethylnonane; and 2-ethoxy-9-(p-sec.-butylphenyl)-2,6-dimethylnonane.
 5. A method of inhibiting the eclosion of fly pupae comprising feeding to cattle from about 0.125 mg to about 2.5 mg per kilogram of body weight per day of a compound of the general formula: ##STR16## in which A is alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, or nitro; R and R¹ are independently methyl or ethyl; and, R² is alkyl having 1 to 4 carbon atoms; said feeding serving to incorporate an eclosion inhibiting amount of said compound in a natural growth media, cattle feces, of the fly pupae.
 6. The method of claim 5 in which A is in the para position.
 7. The method of claim 5 in which the pupae is that of flies selected from the species consisting of the face fly, the house fly, the stable fly and the horn fly.
 8. The method of claim 7 in which the compound is selected from the group consisting of 2-ethoxy-9-(p-ethylphenyl)-2,6-dimethylnonane and 2-ethoxy-9-(p-isopropylphenyl)-2,6-dimethylnonane.
 9. A method of inhibiting the eclosion of fly pupae comprising spraying the growth media of said pupae with an emulsifiable concentrate containing about 25% of a compound of the general formula: ##STR17## in which A is alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, or nitro; R and R¹ are independently methyl or ethyl; and R² is alkyl having 1 to 4 carbon atoms; said compound being applied to the growth media at a rate of from 5 to 500 mg per square foot.
 10. The method of claim 9 in which A is in the para position.
 11. The method of claim 9 in which the pupae is that of flies selected from the group consisting of the stable fly and the house fly.
 12. The method of claim 11 in which the compound is selected from the group consisting of 2-ethoxy-9-(p-ethylphenyl)-2,6-dimethylnonane and 2-ethoxy-9-(p-isopropylphenyl)-2,6-dimethylnonane.
 13. A method of inhibiting the eclosion of pupae of the mosquito, Anopheles quadrimaculatus, comprising applying to the growth media of said mosquito an eclosion formula: ##STR18## in which A is alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, or nitro; R and R¹ are independently methyl or ethyl; and, R² is alkyl having 1 to 4 carbon atoms.
 14. The method of claim 13 in which A is in the para position.
 15. The method of claim 13 in which from about 0.0004 ppm to about 0.0245 ppm of the compound is applied to the growth media.
 16. The method of claim 15 in which the compound is selected from the group consisting of 2-methoxy-9-(p-ethylphenyl)-2,6-dimethylnonane; 2-ethoxy-9-(p-ethylphenyl)-2,6-dimethylnonane; 2-methoxy-9-(p-isopropylphenyl)-2,6-dimethylnonane; and, 2-ethoxy-9-(p-isopropylphenyl)-2,6-dimethylnonane. .Iadd.
 17. A method of inhibiting the eclosion of insect pupae comprising:adding to the habitat of said pupae an inhibiting amount of a compound selected from the group consisting of 2-methoxy-9-(p-ethylphenyl)-2,6-dimethylnonane, 2-ethoxy-9-(p-ethylphenyl)-2,6-dimethylnonane, 2-methoxy-9-(p-isopropylphenyl)-2,6-dimethylnonane and 2-ethoxy-9-(p-isopropylphenyl)-2,6-dimethylnonane supported on an inert diluent carrier, said pupae being susceptible to maturation inhibition by said compound. .Iaddend..Iadd.18. The method of claim 17, wherein said compound is 2-methoxy-9-(p-isopropylphenyl)-2,6-dimethylnonane. .Iaddend. 